Nebivolol is the generic name of ((±))-(R*(S*(S*—(S*))))-(alpha),(alpha)′-(iminobis(methylene)bis-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol). The general structure of nebivolol as it's hydrochloride salt is shown as Formula (a).

Nebivolol is a ß1-adrenoceptor blocking drug, or ß-blocker, distinguished from other members of its drug class by its additional nitric oxide (NO)-mediated vasodilatory effects. Consequently, as well as effectively lowering blood pressure by blocking ß1-adrenoceptors in the heart and vasculature, nebivolol may also slow or prevent some of the vascular complications associated with hypertension, by improving arterial compliance and reducing peripheral vascular resistance. Nebivolol is described as a mixture of equal amounts of 2 enantiomers having respectively the SRRR- and the RSSS-configuration. The SRRR-configuration is a potent and selective ß1-adrenergic antagonist both in vitro and in vivo. Nebivolol can be distinguished from other ß-adrenergic antagonists because it acutely lowers blood pressure in spontaneously hypertensive rats, decreases total peripheral vascular resistance and augments stroke volume in anaesthetized dogs. These haemodynamic effects are largely attributable to the RSSS-configuration of nebivolol. It was also discovered that RSSS-nebivolol is a potentiator for a series of antihypertensive agents such as atenolol, propanolol, prazosin, hydralazine and, interestingly, also its own enantiomer, i.e., the SRRR-configuration. Several clinical trials have also demonstrated the therapeutic potential of nebivolol as a ß1-selective beta-blocker and antihypertensive agent.
Nebivolol as it's hydrochloride salt is available in a tablet dosage form and sold in the UK as Nebilet® for the treatment of mild to moderate essential hypertension in humans.
Methods of preparing Nebivolol and pharmaceutically acceptable salts are described generally in EP 0 145 067 and more specifically in EP 0 334 429 which are incorporated herein by reference.
EP 0 145 067 generally describes 2,2′-iminobisethanol derivatives useful for the treatment and/or prevention of disorders of the coronary vascular system.
EP 0 334 429 describes (iminobismethylene)bis(3,4-dihydro-2H-1-benzopyran-2-methanol) derivatives including nebivolol and pharmaceutically acceptable salts.
As Nebivolol has basic properties it may be converted into its pharmaceutically acceptable acid addition salt forms by treatment with appropriate acids. Appropriate acids are, for example, inorganic acids, such as the hydrochloride or hydrobromide.
EP 0 744 946 B1 by Eugeen et al, incorporated herein by reference, discloses suitable solid and semi-solid pharmaceutical compositions comprising inter alia nebivolol and pharmaceutically acceptable salts for use as antihypertensive agents. Dosage forms include powders, pills, capsules, tablets, suppositories, creams, gels, ointments. Tablets are a particularly preferred solid oral dosage form. The specification describes that oral administration of nebivolol hydrochloride was impeded by the poor dissolution when in a “normal” crystalline form.
A very important factor influencing the bioavailability of active ingredients after oral administration is the dissolution or, more particularly, the rate of dissolution of the active ingredient or drug substance, particularly in gastric fluid. It is recognized in the art that the dissolution for solid dosage forms, particularly tablets, should amount to at least 75% in 45 minutes in 0.1 M Hydrochloric acid at a temperature of 37° C. as measured according to test procedures described in the official pharmacopoeias known to those skilled in the art, e.g., the U.S. Pharmacopoeia XXII.
Investigations towards improving the dissolution and bioavailability of nebivolol hydrochloride led to compositions prepared using nebivolol hydrochloride having a reduced particle size (EP 0 744 946). However the inventors found that after performing a comparative dissolution test comparing the extent of dissolution of “normal” crystalline material with “micronized” nebivolol hydrochloride, the dissolution of the micronized material was described as even worse than material in the normal crystalline form. EP 0 744 946 teaches that the specific area of the micronized material is at least about 23×103 cm2/g (2.3×103 m2/kg), preferably more than 25×103 cm2/g (2.5×103 m2/kg), more preferably more than 28×103 cm2/g (2.8×103 m2/kg), and most preferably more than 31×103 cm2/g (3.1×103 m2/kg). Alternatively the micronized material was described in the following way; at most 50% of the particles may have a diameter larger than 10 μm, i.e. the DL50 has a maximum value of 10 μm. Preferably the DL50 should amount to less than 8 μm. At most 10% of the particles may have a diameter larger than 20 μm, i.e. the DL10 has a maximum value of 20 μm. Preferably the DL10 should amount to less than 18 μm.
Following investigation, the dissolution characteristics of nebivolol hydrochloride in an oral dosage form were apparently improved by formulating micronized material with a wetting agent where the ratio (w/w) of wetting agent/active ingredient ranged between 0.025 and 0.5.
Hence, in summary, the invention disclosed in EP 0 744 946 emphasized that in order to achieve the required pharmacopoeial dissolution, the nebivolol hydrochloride needed to be micronized and sufficiently wet. Wetting was achieved through the inclusion of a wetting agent within the aforesaid ratio. This ratio was described as being an important factor because on the one hand the percentage level of wetting agent needs to be sufficient to influence the desired dissolution but not at the expense of undesirable tablet hardness that affects production on a commercial scale. When the level of wetting agent is too high, resulting tablets do not have the appropriate hardness. Additionally it is known in the art that high levels of wetting agents in pharmaceutical formulations are linked to undesirable effects in humans e.g. permeability enhancement and local damage are closely related sequele of the interaction of surfactants with the intestinal wall (Swenson E S et al; Pharm Res 1994 Aug. 11(8) p 1132-42). Ingested wetting agents may influence the penetration of potentially toxic compounds (Liebermann H. A. et al Pharmaceutical Dosage Forms: Disperse Systems, 2nd Ed, Vol 1, page 261).
“Micronization” as used herein is a generic term for the process where the mean particle size of a particular drug substance is reduced by mechanical means which increases the surface area of the particles available for contact with biological fluids. Micronization can be carried out by known techniques such as milling or sieving through appropriate sieves; see Pharmaceutical Dosage Forms: Vol 2, 1990; H A Lieberman, page 107. However, these techniques are time consuming and uneconomic when the objective is to prepare pharmaceutical dosage forms comprising nebivolol hydrochloride on a commercial scale that also complies with rigorous internal and external quality control requirements.
Furthermore the known processes of micronization may be unsuitable for thermolabile or physically unstable drug substances leading to undesirable degradation of the material under investigation. Fine powder particles also create potentially dangerous dust conditions which require operators to wear respirators for safe handling; Lachman & Liebrman, Pharmaceutical Dosage Forms: Tablets, Vol 2, second edition, 1990, page 35.
WO 2006/025070 to Sheth R et al and incorporated herein discloses inter alia pharmaceutical compositions comprising nebivolol hydrochloride e.g., tablets and capsules without using a wetting agent.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.